ProjectSummary/Abstract Malariaisasignificantglobalhealthprobleminwhichwestillfailtounderstandmany protectivefeaturesoftheimmuneresponse.Naturalkiller(NK)cellsproduce inflammatorycytokinesduringtheearlystagesofinfection,yethavealsobeenshownin viralmodelstolimitTcellandBcellresponses.WerecentlydemonstratedthatNKcell- producedIL-10canlimitCD8+Tcellactivityduringexperimentalcerebralmalariaand therebyrescuemicefromfatal,CD8+Tcell-mediatedimmunopathology.Usingnewly generatedmousestrains,wewillvisualthelocationandcellularinteractionsofNKcells inthebrainandestablishthecellulartargetsofNKcell-derivedIL-10duringcerebral disease.OurstudieswillalsodetermineifdistincthumanNKcellsubsetsaremore efficientatproducingIL-10,andifthesecellscorrelatewithprotectionfrommalaria symptomsinhumans.Finally,wewillinvestigatetheimpactofNKcell-derivedIL-10on thedevelopmentandfunctionofmemoryCD8+Tcells.Ourobjectiveistounderstand howNKcellregulatoryfunctionslikeIL-10productiondecreaseimmunopathologyand symptomaticinfection,andshapethedevelopingTcellresponse.Theproposedwork willdeterminetheconsequencesofNKcell-derivedIL-10duringtheimmuneresponse tomalariaandrevealwaystoexploitregulatoryNKcellfunction,therebyimproving immunityinpopulationsatriskforseveredisease.